Summary: The prion protein (PrP), which is thought to be the infectious agent in the fatal neurodegenerative diseases called transmissible spongiform encephalopathies (TSE), is expressed on many cell types including macrophages. Specific peptides derived from the PrP sequence have been examined for their potential cytotoxic and neurotoxic effects when used in vitro or in-vivo. One such peptide, the PrP106-126 fragment has been shown to mimic the pathologic isoform of prion protein and to induce a cytotoxic effect in neuronal cells. To characterize the role of monocytes and monocyte-derived cells in this process and to determine the potential mechanism whereby this cytotoxicity can occur, we are determining the ability of PrP106-126 to activate specific signalling pathways in monocytes and dendritic cells derived from elutriated human monocytes. Our data demonstrate that dendritic cells exposed to PrP106-126 undergo an activation of intrinsic NFkB, as demonstrated by electrophoretic mobility shift assays. Activation of NFkB is observed within 30 minutes of exposure, with a maximum activation seen at 120 minutes. Because NFkB is involved in the regulation of inflammatory mediators, we are also analyzing inflammatory cytokine gene expression in dendritic cells responding to PrP106-126. Preliminary data indicate a marked induction of mRNA for IL-1alpha, IL-6, and TNFalpha in a time-dependent manner. This increased expression of mRNA is being compared to ELISA data to determine the concomitant accumulation of the specific protein in the culture supernatant. These data demonstrate the ability of prion protein fragments to induce inflammatory cytokines through the NFkB signalling pathway and suggest a potential mechanism by which prion proteins may exert their neuro- and cytotoxicity.